Variant of TREM2 associated with the risk of Alzheimer's disease.
Variant of TREM2 associated with the risk of Alzheimer's disease.
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DOI：
10.1056/nejmoa1211103
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发表时间：
2013-01-10
期刊：
影响因子：
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通讯作者：
Stefansson K
中科院分区：
文献类型：
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作者：
Jonsson T;Stefansson H;Steinberg S;Jonsdottir I;Jonsson PV;Snaedal J;Bjornsson S;Huttenlocher J;Levey AI;Lah JJ;Rujescu D;Hampel H;Giegling I;Andreassen OA;Engedal K;Ulstein I;Djurovic S;Ibrahim-Verbaas C;Hofman A;Ikram MA;van Duijn CM;Thorsteinsdottir U;Kong A;Stefansson K
序列变异，包括载脂蛋白E的ε4等位基因，与常见的晚发性阿尔茨海默病的风险有关。已经发现了一些影响晚发性阿尔茨海默病风险的罕见变异。我们获得了2261名冰岛人的基因组序列，并确定了可能影响蛋白质功能的序列变异。我们将这些变异输入到阿尔茨海默病患者和对照组的基因组中，然后测试与阿尔茨海默病的关联。我们使用来自美国、挪威、荷兰和德国的病例对照系列进行了重复试验。我们还在未受影响的老年人群体中测试了与认知功能的遗传关联。在冰岛，一种罕见的编码髓样细胞2 （TREM2）上表达的触发受体的基因错义突变（rs75932628-T）被发现具有显著的阿尔茨海默病风险（优势比为2.92；95%置信区间[CI]， 2.09至4.09;P = 3.42×10−10），该突变被预测会导致R47H替代。在85岁及以上的对照组中，该突变的频率为0.46%。我们在其他样本集中观察到这种关联（比值比为2.90；95% CI为2.16至3.91；在发现和复制联合样本中P = 2.1×10−12）。我们还发现，年龄在80岁至100岁之间，无阿尔茨海默病的rs75932628-T携带者的认知功能比非携带者差（P = 0.003）。我们的研究结果强烈暗示tre2变异与阿尔茨海默病的发病机制有关。鉴于已报道的TREM2在大脑中的抗炎作用，R47H替代可能通过抑制炎症过程导致阿尔茨海默病的易感性增加。（由美国国家老龄化研究所和其他机构资助。）
Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer’s disease. Few rare variants affecting the risk of late-onset Alzheimer’s disease have been found. We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer’s disease and control participants and then tested for an association with Alzheimer’s disease. We performed replication tests using case–control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer’s disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10−12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers (P = 0.003). Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.)